Neurotensin and cholecystokinin have both demonstrated "neuroleptic- like" properties when tested in animal studies. Both of these peptides are contained in CNS projections to brain regions associated with behavior and alterations in CCK and NT levels have been reported in post-mortem brains from patients diagnosed with schizophrenia. These data together with the close morphological association of CCK and NT with dopamine leads us to speculate that there is a role for NT and CCK in schizophrenia. Antipsychotic drugs used to treat schizophrenia have also shown a well documented effect on CCK and NT brain levels and metabolic enzymes. Since the metabolic rates of peptide precursors are generally determined by the specific peptidases associated with peptide metabolism, insight into the mechanisms controlling CCK and NT metabolism in neuronal systems can further elucidate the role of CCK and NT in the brain with respect to mental disease. The hypothesis that we will test is that metabolic enzymes associated with CCK and NT-producing cells can be affected by antipsychotic drugs. Among the mechanisms proposed for modulation of peptidergic systems by antipsychotic drugs has been the regulation of the rate of peptide degradation at its site of action. In turn, enzymatic hydrolysis may also result in the formation of new and biologically active peptide fragments by the same enzymes. Therefore, proteolytic enzymes play a crucial role in peptidergic systems. Consequently, experiments in CCK-and NT areas of the brain in vivo in rats exposed to drug treatments are planned to evaluate the physiological significance using intact, discrete, regional brain slices. We are very confident that we will be successful in determining how CCK and NT are affected by antipsychotic drugs.